Polymeric Cups for Cavitation-mediated Delivery of Oncolytic Vaccinia Virus.

Rachel Myers,Constantin Coussios,Edward Jackson,Cliff Rowe,Robert Carlisle,Christian Coviello,Colin Story,Seán Finn,Philippe Erbs,Jean-Marc Balloul,Calum Crake,James Kwan,Johann Foloppe

doi:10.1038/mt.2016.139

Rachel Myers, Constantin Coussios + Show 11 more

Open Access

https://doi.org/10.1038/mt.2016.139

Copy DOI

Journal: Molecular Therapy	Publication Date: Aug 9, 2016
Citations: 51	License type: cc-by

Affiliation: University of Oxford, Transgene (France)

Abstract

Oncolytic viruses (OV) could become the most powerful and selective cancer therapies. However, the limited transport of OV into and throughout tumors following intravenous injection means their clinical administration is often restricted to direct intratumoral dosing. Application of physical stimuli, such as focused ultrasound, offers a means of achieving enhanced mass transport. In particular, shockwaves and microstreaming resulting from the instigation of an ultrasound-induced event known as inertial cavitation can propel OV hundreds of microns. We have recently developed a polymeric cup formulation which, when delivered intravenously, provides the nuclei for instigation of sustained inertial cavitation events within tumors. Here we report that exposure of tumors to focused ultrasound after intravenous coinjection of cups and oncolytic vaccinia virus , leads to substantial and significant increases in activity. When cavitation was instigated within SKOV-3 or HepG2 xenografts, reporter gene expression from vaccinia virus was enhanced 1,000-fold (P < 0.0001) or 10,000-fold (P < 0.001), respectively. Similar increases in the number of vaccinia virus genomes recovered from tumors were also observed. In survival studies, the application of cup mediated cavitation to a vaccinia virus expressing a prodrug converting enzyme provided significant (P < 0.05) retardation of tumor growth. This technology could improve the clinical utility of all biological therapeutics including OV.

Highlights

Oncolytic viruses (OV) represent a powerful platform for achieving cancer therapy due to their tumor-selective self-amplification and their ability to provide expression of therapeutic proteins from within tumors.[1,2] The decade is likely to see a wide range of these agents continuing their progression through the clinical testing pathway both in combination with conventional anticancer strategies[3] and immuno-oncology approaches.[4]
5 days after treatment, mice with HepG2 tumors dosed with cups + VV + US provided more than 125-fold greater luminescent signal compared with those dosed with cups + VV alone (P < 0.05) and sixfold increase over those dosed with SV + VV + US (Figure 1b)
OVs have been approved for use in humans, this is in the context of intratumoral injection,[25,26] a route which restricts potential efficacy[5] and the range of applicable indications

Summary

Introduction

Oncolytic viruses (OV) represent a powerful platform for achieving cancer therapy due to their tumor-selective self-amplification and their ability to provide expression of therapeutic proteins from within tumors.[1,2] The decade is likely to see a wide range of these agents continuing their progression through the clinical testing pathway both in combination with conventional anticancer strategies[3] and immuno-oncology approaches.[4] the poor delivery of OV into and throughout target tumors following systemic administration means that, to date, the majority of

Methods

Results

Conclusion